1. Field of the Invention
The present invention relates to antibiotic pharmaceutical compositions with improved oral absorbability, more specifically to antibiotic pharmaceutical compositions comprising amorphous cefditoren pivoxil.
2. Background Art
An antibiotic compound cefditoren is a cephem compound represented by formula (A):
Its chemical name is (+)-(6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. This compound is described in Japanese Patent Publication No. 64503/1991 under the chemical name of 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid (syn-isomer, cis-isomer).
A pivaloyloxymethyl ester of cefditoren, in which a carboxylic acid group on position 2 of the cephem compound is esterified with a pivaloyloxymethyl group for the purpose of improving its absorbability through the digestive tracts upon oral administration (hereinafter referred to as “oral absorbability”), is called cefditoren pivoxil. This prodrug compound is represented by formula (B):
and its chemical name is (−)-(6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2,2-dimethylpropionyloxymethyl ester. This ester compound is generally considered to exhibit high oral absorbability as compared to the original acid-form drug. However, the esterification of cefditoren has not necessarily resulted in enhancement or improvement of the oral absorbability to the satisfactory level.
In order to improve the oral absorbability of cefditoren pivoxil, a pharmaceutical preparation in which cyclodextrin or hydroxypropyl cellulose that is a water-soluble polymer cellulose derivative is added to cefditoren pivoxil has been proposed (Japanese Patent Publication No. 78234/1994 and Japanese Patent Laid-Open Publication No. 17866/1995). However, the addition of cyclodextrin to cefditoren pivoxil extremely intensified the bitterness derived from cefditoren pivoxil and pharmaceutical tablets or granules obtained with the addition of hydroxypropyl cellulose became bulky, which made oral administration difficult.
In order to solve these problems, a pharmaceutical preparation in which a water-soluble caseinate is added to cefditoren pivoxil has recently been proposed (Japanese Patent No. 2831135). However, this preparation could not be administered to a patient suffering from a milk allergy since casein is a protein derived from milk.
Thus, a pharmaceutical preparation wherein cefditoren pivoxil can be safely administered to a patient and oral absorbability sufficient enough to exert its expected pharmaceutical effect is secured has been in demand.
On the other hand, as a means to improve oral absorbability of a poorly soluble drug, a solid composition which is obtained by amorphousizing the poorly soluble drug in the presence of a polymer base and a nonionic surfactant is disclosed in WO 96/19239. It is disclosed that the above-mentioned composition maintains its amorphousness state when dispersed in a liquid and that the maximum concentration in the blood (Cmax) and the area under the curve of blood concentration (AUC) increase when orally administered to dogs, that is, the oral absorbability can be improved. However, shortening of the time required to reach the maximum blood concentration, which is an index of immediate effect, has not been achieved. Further, the disclosed solid composition is notably characterized in that the drug, the polymer base, and the nonionic surfactant are mixed in a molecular state, namely in a state of solid dispersion composition. Furthermore, such a pharmaceutical preparation is produced using a spray drying method in which a solvent such as dichloromethane is occasionally used, which requires a concern for environment and a security for safety.
Further, Japanese Patent No. 3290970 discloses, as a means to improve oral absorbability of a poorly soluble drug, a solid pharmaceutical preparation containing poorly soluble NSAIDs, a water-soluble polymer base and a nonionic surfactant, which is characterized in that the poorly soluble NSAIDs are in a crystalline state.
Further, WO 99/34832 discloses a composition comprising a crystallographically stable, amorphous cephalosporin and a process for the preparation thereof, indicating that the oral absorbability can be improved by amorphousizing the cephalosporin. Japanese Patent Laid-Open Publication No. 131071/2001 discloses a process for the preparation of amorphous cefditoren pivoxil, in which the oral absorbability can be improved by amorphousizing cefditoren pivoxil. Further, WO 02/87588 discloses a process for producing an amorphous composition, in which an organic polymer is mixed with cefditoren pivoxil crystals and the obtained mixture is ground.